The galectin lattice at a glance Nabi, Ivan R; Shankar, Jay; Dennis, James W
Journal of cell science,
07/2015, Letnik:
128, Številka:
13
Journal Article
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Galectins are a family of widely expressed β-galactoside-binding lectins in metazoans. The 15 mammalian galectins have either one or two conserved carbohydrate recognition domains (CRDs), with ...galectin-3 being able to pentamerize; they form complexes that crosslink glycosylated ligands to form a dynamic lattice. The galectin lattice regulates the diffusion, compartmentalization and endocytosis of plasma membrane glycoproteins and glycolipids. The galectin lattice also regulates the selection, activation and arrest of T cells, receptor kinase signaling and the functionality of membrane receptors, including the glucagon receptor, glucose and amino acid transporters, cadherins and integrins. The affinity of transmembrane glycoproteins to the galectin lattice is proportional to the number and branching of their N-glycans; with branching being mediated by Golgi N-acetylglucosaminyltransferase-branching enzymes and the supply of UDP-GlcNAc through metabolite flux through the hexosamine biosynthesis pathway. The relative affinities of glycoproteins for the galectin lattice depend on the activities of the Golgi enzymes that generate the epitopes of their ligands and, thus, provide a means to analyze biological function of lectins and of the 'glycome' more broadly.
A new surface boundary forcing dataset for uncoupled simulations with the Community Atmosphere Model is described. It is a merged product based on the monthly mean Hadley Centre sea ice and SST ...dataset version 1 (HadISST1) and version 2 of the National Oceanic and Atmospheric Administration (NOAA) weekly optimum interpolation (OI) SST analysis. These two source datasets were also used to supply ocean surface information to the 40-yr European Centre for Medium-Range Weather Forecasts Re-Analysis (ERA-40). The merged product provides monthly mean sea surface temperature and sea ice concentration data from 1870 to the present: it is updated monthly, and it is freely available for community use. The merging procedure was designed to take full advantage of the higher-resolution SST information inherent in the NOAA OI.v2 analysis.
Neurobiology of resilience Russo, Scott J; Murrough, James W; Han, Ming-Hu ...
Nature neuroscience,
11/2012, Letnik:
15, Številka:
11
Journal Article
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Humans exhibit a remarkable degree of resilience in the face of extreme stress, with most resisting the development of neuropsychiatric disorders. Over the past 5 years, there has been increasing ...interest in the active, adaptive coping mechanisms of resilience; however, in humans, most published work focuses on correlative neuroendocrine markers that are associated with a resilient phenotype. In this review, we highlight a growing literature in rodents that is starting to complement the human work by identifying the active behavioral, neural, molecular and hormonal basis of resilience. The therapeutic implications of these findings are important and can pave the way for an innovative approach to drug development for a range of stress-related syndromes.
The response to DNA damage is critical for cellular homeostasis, tumor suppression, immunity, and gametogenesis. In order to provide an unbiased and global view of the DNA damage response in human ...cells, we undertook 31 CRISPR-Cas9 screens against 27 genotoxic agents in the retinal pigment epithelium-1 (RPE1) cell line. These screens identified 890 genes whose loss causes either sensitivity or resistance to DNA-damaging agents. Mining this dataset, we discovered that ERCC6L2 (which is mutated in a bone-marrow failure syndrome) codes for a canonical non-homologous end-joining pathway factor, that the RNA polymerase II component ELOF1 modulates the response to transcription-blocking agents, and that the cytotoxicity of the G-quadruplex ligand pyridostatin involves trapping topoisomerase II on DNA. This map of the DNA damage response provides a rich resource to study this fundamental cellular system and has implications for the development and use of genotoxic agents in cancer therapy.
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•Resource of 31 genome-scale CRISPR screens against DNA-damaging agents•Cytotoxicity of G-quadruplex ligand pyridostatin involves TOP2 trapping•The bone-marrow failure syndrome gene ERCC6L2 codes for an NHEJ factor•The ELOF1 and STK19 proteins are candidate TC-NER factors
A set of CRISPR screens in cells treated with different genotoxic agents illuminates the cellular response to DNA damage, identifying new factors in several repair pathways and pinpointing a novel drug mechanism-of-action.
A primary target of the pleiotropic metabolic hormone FGF21 is adipose tissue, where it initiates a gene expression program to enhance energy expenditure, an effect presumed to be centered on ...augmented UCP1 expression and activity. In UCP1 null (UCP1KO) mice, we show that the effect of FGF21 to increase the metabolic rate is abolished. However, in contrast to prior expectations, we found that increased UCP1-dependent thermogenesis is only partially required to achieve the beneficial effects of FGF21 treatment. In UCP1KO mice, there appears to be an underlying reduction in food intake following FGF21 administration, facilitating weight loss equal to that observed in wild-type animals. Furthermore, we show that UCP1-dependent thermogenesis is not required for FGF21 to improve glycemic control or to reduce circulating cholesterol or free fatty acids. These data indicate that several important metabolic endpoints of FGF21 are UCP1 independent; however, the contribution of UCP1-dependent thermogenesis to other discrete aspects of FGF21 biology requires further study.
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•In UCP1KO mice, FGF21 acts to reduce food intake to promote weight loss•The majority of FGF21-driven metabolic endpoints do not require UCP1•FGF21 requires the presence of UCP1 to enhance caloric expenditure in vivo
FGF21 is a metabolic regulator whose effects are associated with increases in UCP1 and energy expenditure. To delineate the contribution of uncoupled respiration to the pharmacology of FGF21, Samms et al. examine its effects in UCP1 null mice. They report that the majority of metabolic effects triggered by FGF21 occur independently of UCP1.
Maintenance of the proteasome requires oxidative phosphorylation (ATP) and mitigation of oxidative damage, in an increasingly dysfunctional relationship with aging. SLC3A2 plays a role on both sides ...of this dichotomy as an adaptor to SLC7A5, a transporter of branched-chain amino acids (BCAA: Leu, Ile, Val), and to SLC7A11, a cystine importer supplying cysteine to the synthesis of the antioxidant glutathione. Endurance in mammalian muscle depends in part on oxidation of BCAA; however, elevated serum levels are associated with insulin resistance and shortened lifespans. Intriguingly, the evolution of modern birds (Neoaves) has entailed the purging of genes including SLC3A2, SLC7A5, -7, -8, -10, and SLC1A4, -5, largely removing BCAA exchangers and their interacting Na+/Gln symporters in pursuit of improved energetics. Additional gene purging included mitochondrial BCAA aminotransferase (BCAT2), pointing to reduced oxidation of BCAA and increased hepatic conversion to triglycerides and glucose. Fat deposits are anhydrous and highly reduced, maximizing the fuel/weight ratio for prolonged flight, but fat accumulation in muscle cells of aging humans contributes to inflammation and senescence. Duplications of the bidirectional α-ketoacid transporters SLC16A3, SLC16A7, the cystine transporters SLC7A9, SLC7A11, and N-glycan branching enzymes MGAT4B, MGAT4C in Neoaves suggests a shift to the transport of deaminated essential amino acid, and stronger mitigation of oxidative stress supported by the galectin lattice. We suggest that Alfred Lotka’s theory of natural selection as a maximum power organizer (PNAS 8:151,1922) made an unusually large contribution to Neoave evolution. Further molecular analysis of Neoaves may reveal novel rewiring with applications for human health and longevity.
Genetic information flows from DNA to macromolecular structures—the dominant force in the molecular organization of life. However, recent work suggests that metabolite availability to the hexosamine ...and Golgi N-glycosylation pathways exerts control over the assembly of macromolecular complexes on the cell surface and, in this capacity, acts upstream of signaling and gene expression. The structure and number of N
-glycans per protein molecule cooperate to regulate lectin binding and thereby the distribution of glycoproteins at the cell surface. Congenital disorders of glycosylation provide insight as extreme hypomorphisms, whereas milder deficiencies may encompass many common chronic conditions, including autoimmunity, metabolic syndrome, and aging.
Depression is a common problem in patients with cardiovascular disease (CVD) and is associated with increased mortality, excess disability, greater health care expenditures, and reduced quality of ...life. Depression is present in 1 of 5 patients with coronary artery disease, peripheral artery disease, and heart failure. Depression complicates the optimal management of CVD by worsening cardiovascular risk factors and decreasing adherence to healthy lifestyles and evidence-based medical therapies. As such, standardized screening pathways for depression in patients with CVD offer the potential for early identification and optimal management of depression to improve health outcomes. Unfortunately, the burden of depression in patients with CVD is under-recognized; as a result, screening and management strategies targeting depression have been poorly implemented in patients with CVD. In this review, the authors discuss a practical approach for the screening and management of depression in patients with CVD.
Posttraumatic stress disorder (PTSD) is a chronic and disabling disorder, for which available pharmacotherapies have limited efficacy. The authors' previous proof-of-concept randomized controlled ...trial of single-dose intravenous ketamine infusion in individuals with PTSD showed significant and rapid PTSD symptom reduction 24 hours postinfusion. The present study is the first randomized controlled trial to test the efficacy and safety of repeated intravenous ketamine infusions for the treatment of chronic PTSD.
Individuals with chronic PTSD (N=30) were randomly assigned (1:1) to receive six infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) (psychoactive placebo control) over 2 consecutive weeks. Clinician-rated and self-report assessments were administered 24 hours after the first infusion and at weekly visits. The primary outcome measure was change in PTSD symptom severity, as assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), from baseline to 2 weeks (after completion of all infusions). Secondary outcome measures included the Impact of Event Scale-Revised, the Montgomery-Åsberg Depression Rating Scale (MADRS), and side effect measures.
The ketamine group showed a significantly greater improvement in CAPS-5 and MADRS total scores than the midazolam group from baseline to week 2. At week 2, the mean CAPS-5 total score was 11.88 points (SE=3.96) lower in the ketamine group than in the midazolam group (d=1.13, 95% CI=0.36, 1.91). Sixty-seven percent of participants in the ketamine group were treatment responders, compared with 20% in the midazolam group. Among ketamine responders, the median time to loss of response was 27.5 days following the 2-week course of infusions. Ketamine infusions were well tolerated overall, without serious adverse events.
This randomized controlled trial provides the first evidence of efficacy of repeated ketamine infusions in reducing symptom severity in individuals with chronic PTSD. Further studies are warranted to understand ketamine's full potential as a treatment for chronic PTSD.
The role of epigenetics in hybrid vigour Groszmann, Michael; Greaves, Ian K; Fujimoto, Ryo ...
Trends in genetics,
12/2013, Letnik:
29, Številka:
12
Journal Article
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Highlights • Hybrids with similar genome sequences can show significant heterosis. • The final level of heterosis, either in biomass or grain yield, is dependent on changes that occur throughout ...development. • Hybrids exhibit increased levels of transcription of chloroplast-targeted genes and increases in the size and/or number of photosynthetic cells in cotyledons and early true leaves. • Hybrids show changed 24-nucleotide small interfering RNA levels in localized regions of the genome and altered DNA methylation patterns, which may account for differences in gene expression.
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